| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Heart Failure with reduced ejection fraction and borderline systolic blood pressure. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Heart Failure with reduced ejection fraction and borderline systolic blood pressure. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10007541 |
| E.1.2 | Term | Cardiac disorders |
| E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess whether reducing heart rate with Ivabradine, versus further titration of beta blockade, in patients with HF-REF and borderline systolic blood pressure results in improved 6MWT |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the effect of reducing heart rate with Ivabradine, versus further titration of beta blockade in patients with HF-REF and borderline systolic blood pressure on:
•Quality of Life (KCCQ)
•Other clinical outcomes (NYHA status, Cardiovascular exams, BNP and eGFR)
•Becks Depression Score; and
•To evaluate the safety follow-up in both groups
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Recently prescribed the beta-blocker bisoprolol or carvedilol (a maximum of 4 weeks since initiating treatment and at least one week for bisoprolol and at least two weeks for carvedilol since the last BB dose adjustment with doses not greater than bisoprolol 5mg daily/carvedilol 12.5mg twice daily, to allow further up-titration)
•Willing to give written informed consent to participate in the study and to comply with the study procedures and restrictions during the study period.
•Male or female ≥ 18 years
•Diagnosed with symptomatic HF-REF and LVEF ≤ 40% (measured no longer than 3 months before the selection visit)
•Systolic CHF class II and III (NYHA class)
•No evidence of clinical decompensation
•Electrocardiographic documentation of sinus rhythm with resting heart rate ≥ 70bpm
•SBP ≤120mmHg and ≥100mmHg
•Able to walk more than 450 meters within 6 minutes during inclusion visit (INCL)
•Recently prescribed the beta-blockers bisoprolol or carvedilol and undergoing BB titration (at least one week for bisoprolol and at least two weeks for carvedilol since the last BB dose adjustment), with dose not greater than bisoprolol 5mg daily/carvedilol 12.5mg twice daily, to allow further up-titration)
•Having completed other drug titration so as to confine the drug manipulation during the study period to a minimum (eg on full dose ACEi/ARB)
•ICD implantation is acceptable for inclusion. The presence of a CRT device will be assessed on a case by case basis
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| E.4 | Principal exclusion criteria |
•Participation in another study at the same time or within three months prior the selection visit (ASSE) for this study
•Unable to provide written informed consent
•Women who are pregnant or breast-feeding or women of child bearing potential not using estro-progestative oral or intra-uterine contraception or implants, or women using estro-progestative oral or intra-uterine contraception or implants but who consider stopping it during the planned duration of the study. Menopause will be defined as absence of menses for ≥ 1 year.
•Current treatment with beta blocker other than bisoprolol or carvedilol
•Current treatment with ivabradine or previous treatment in the last 6 months
•Resting heart rate <70 beats per minute
•Able to walk more than 450 meters within 6 minutes during inclusion visit (INCL)
•History of drug or alcohol use that, in the opinion of the investigator, would interfere with adherence to study requirements
•Known severe renal insufficiency with calculated creatinine clearance ≤15 mL/min/1.732
•Severe hepatic insufficiency
•Any other significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk by participation in the study, or may influence the result of the study
•Prior or concurrent malignancy within 5 years prior to starting the study treatment
•Known contraindication/allergy/sensitivity/intolerance to study medications or their ingredients (Ivabradine, Bisoprolol and/or Carvedilol)
•Documented permanent atrial fibrillation or other cardiac arrhythmia that interferes with the sinus node function, or recent hospitalisation for atrial fibrillation or other cardiac arrhythmia that interfere with the sinus node function within the last 3 months
•Severe hypotension (<90/50 mmHg)
•Cardiogenic shock
•Sick sinus syndrome, sino-atrial block, 2nd and 3rd degree AV-block
•Unstable or acute heart failure
•Unstable angina
•Recent myocardial infarction or coronary revascularisation (less than 2 months),
•Pacemaker dependent
•Other clinically significant ECG findings as judged by the investigator
•Patients with familial history or congenital or substance-induced long QT syndrome or treated with selected QT prolonging products (see section 12.9)
•Scheduled for procedures requiring general anaesthesia during the study
•Clinically significant abnormalities as judged by the investigator in haematology and biochemistry parameters. Special attention should be given to potentially significant abnormal values of the renal or liver function test
•Clinically significant findings as judged by the investigator during the procedures performed at the selection or inclusion visits
•Any treatment with unauthorised medications (see section 12.9) that could not be interrupted for the duration of the study
•Patients requiring a treatment that is unauthorised during the study or for whom such a treatment is considered
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Difference in meters between the 6MWT performed at baseline (INCL) and at week 18 (W18) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Functional status summary score of the Kansas City Cardiomyopathy Questionnaire (KCCQ) assessed at baseline (INCL) and at end of study visit (W18)
•Other domain scores of the KCCQ assessed at baseline (INCL) and at end of study visit (W18)
•Functional capacity (NYHA class) and clinical symptoms of heart failure assessed during the study
•Clinical outcomes assessed during the study
•BNP measured at baseline (INCL) and at end of study visit (W18)
•Renal function assessed at baseline (INCL) and at end of study visit (W18)
•Becks Depression Score assessed at baseline (INCL) and at end of study visit (W18)
•Number/Time to occurrence of the first event of one of the following: Patient death from any cause, Hospitalisation for any cause, Emergency room visits for any cause, and Out-patients visits for management of clinical deterioration of Heart Failure.
•Adverse event recording (Safety follow-up)
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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